Microtubules are dynamic polymers of α and β-tubulin present in the Eukaryotic cells that play an important role in most of the fundamental cellular processes such as cell division, motility, transport, and maintenance of cell shape. Colchicines (S1), combretastatin (S2) nocodazole (S3) and podophyllotoxins (S4) are the distinguished compounds that inhibit microtubule assembly by binding at colchicine binding site of the tubulin.
Benzimidazole scaffold is the most privileged structure in the field of medicinal chemistry and this residue is a constituent of vitamin B12 that further supports its potential for their development as therapeutic agents. Recently high-throughput virtual screening was performed wherein 2-aryl benzimidazoles were identified as multi-target EGFR, VEGFR-2 and PDGFR inhibitors with improved therapeutic efficacies. (Li Y, Tan C, Gao C, Zhang C, Luan X, Chen X, Liu H, Chen Y, Jiang Y. Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors. Bioorg. Med. Chem. 2011 19, (15), 4529-4535). A recent report suggests that terphenyl benzimidazoles inhibit the tubulin polymerization with arrest in G2/M phase of cell cycle. (Kamal A, Reddy M K, Shaik T B, Rajender, Srikanth Y V, Reddy V S, Kumar G B, Kalivendi S V. Synthesis of terphenyl benzimidazoles as tubulin polymerization inhibitors. Eur. J. Med. Chem, 2012, 50, 9-17). On other hand the pyrazole derivatives received considerable attention owing to their diverse chemotherapeutic potentials including versatile antineoplastic activities and some pyrazoles have been developed as antitumor and antiproliferative agents, they exert anticancer activity by inhibiting different types of enzymes that play major role in cell division. (El-Dakdouki M H, Adamski N, Foster L, Hacker M P, Erhardt P W. Hypoxia activated prodrugs of a 9-aza-anthrapyrazole derivative that has promising anticancer activity. J. Med. Chem. 2011, 54, (23), 8224-8227). Moreover tri and tetra substituted pyrazole derivates have been proved to have potent anticancer action due to the inhibition of p38α MAP kinase (Abu Thaher B, Arnsmann M, Totzke F, Ehlert J E, Kubbutat M H, Schächtele C, Zimmermann M O, Koch P, Boeckler F M, Laufer S A. Tri- and tetrasubstituted pyrazole derivates: regioisomerism switches activity from p38MAP kinase to important cancer kinases. J. Med. Chem. 2012, 55, (2), 961-965). Many reports suggest that methoxy substituents of combretastatin play a major role in the tubulin depolymerisation process by binding at colchicine binding site, thus incorporating such a component has been utilized extensively to design the pharmacophore that target tubulin (Congiu C, Onnis V, Vesci L, Castorina M, Pisano C. Synthesis and in vitro antitumor activity of new 4,5-dihydropyrazole derivatives. Bioorg. Med. Chem. 2010, 18, (17), 6238-6248). The exceptional feature of microtubule-binding agents, in comparison to other categories of anticancer drugs, is their incredible structural complexity and diversity, which provides many possibilities for new scaffold design. Recently, many studies suggested that combination chemotherapy with the drugs that could work by different mechanism. Therefore, conjugates of pyrazole and benzimidazole have been designed to evaluate anticancer activity that could be beneficial for the treatment of cancer.
However, there still remains a need in the industry for effective and novel anticancer drugs.